First-Episode Psychosis Patients Who Deteriorated in the Premorbid Period Do Not Have Higher Polygenic Risk Scores Than Others: A Cluster Analysis of EU-GEI Data

Abstract

Cluster studies identified a subgroup of patients with psychosis whose premorbid adjustment deteriorates before the onset, which may reflect variation in genetic influence. However, other studies reported a complex relationship between distinctive patterns of cannabis use and cognitive and premorbid impairment that is worthy of consideration. We examined whether: (1) premorbid social functioning (PSF) and premorbid academic functioning (PAF) in childhood and adolescence and current intellectual quotient (IQ) define different clusters in 802 first-episode of psychosis (FEP) patients; resulting clusters vary in (2) polygenic risk scores (PRSs) for schizophrenia (SCZ_PRS), bipolar disorder (BD_PRS), major depression (MD_PRS), and IQ (IQ_PRS), and (3) patterns of cannabis use, compared to 1,263 population-based controls. Four transdiagnostic clusters emerged (BIC = 2268.5): (1) high-cognitive-functioning (n = 205), with the highest IQ (Mean = 106.1, 95% CI: 104.3, 107.9) and PAF, but low PSF. (2) Low-cognitive-functioning (n = 223), with the lowest IQ (Mean = 73.9, 95% CI: 72.2, 75.7) and PAF, but normal PSF. (3) Intermediate (n = 224) (Mean_IQ = 80.8, 95% CI: 79.1, 82.5) with low-improving PAF and PSF. 4) Deteriorating (n = 150) (Mean_IQ = 80.6, 95% CI: 78.5, 82.7), with normal-deteriorating PAF and PSF. The PRSs explained 7.9% of between-group membership. FEP had higher SCZ_PRS than controls [F(4,1319) = 20.4, P < .001]. Among the clusters, the deteriorating group had lower SCZ_PRS and was likelier to have used high-potency cannabis daily. Patients with FEP clustered according to their premorbid and cognitive abilities. Pronounced premorbid deterioration was not typical of most FEP, including those more strongly predisposed to schizophrenia, but appeared in a cluster with a history of high-potency cannabis use.

Studying the relationship between intelligence quotient and schizophrenia polygenic scores in a family design with first-episode psychosis population

“…We confirmed a strong association between PGS-IQ and IQ. This association has been previously reported in the general population [ 19 , 22 ], and our study replicates it in the FEP population [ 25 , 65 ]. As expected, polymorphic genetic factors explain a small percentage of the variance in IQ, suggesting that there is a very large amount of variability associated not only with other sources of genomic variability but also with environmental factors.…”

“…This supports the efficacy of the PGS method in discerning varying levels of genetic predisposition to psychosis. While previous research indicates that PGS-SCZ can differentiate between FEP patients and controls [25,26], our findings suggest that it can also detect genetic risk variation within families. Although FEP patients showed PGS-IQ similar to other groups, their IQ scores were lower, suggesting unachieved cognitive potential.…”

“…On the other hand, polygenic risk scores for schizophrenia (PGS-SCZ) can be calculated leveraging the results of genome-wide studies on this disorder [ 23 , 24 ]. PGS-SCZ explain between 2.4% and 7.3% of the variance in SCZ on the liability scale [ 23 , 24 ] and is increased in FEP patients compared to controls [ 25 , 26 ]. There may be a certain degree of association between these two PGSs, given that numerous genetic variants have been identified as contributing factors to intelligence and SCZ [ 27 , 28 ].…”

Cognitive impairment in schizophrenia: aetiology, pathophysiology, and treatment

“…However, among people with schizophrenia, some studies have reported that cannabis users show better cognitive performance than patients who are non-users [127,128]. This finding appears counter-intuitive, as cannabis use in healthy volunteers and other studies in schizophrenia has been associated with impairments in cognitive function [125,129,130]. The association with better performance in schizophrenia may depend on the pattern of cannabis use, as it is mainly evident in infrequent users rather than in regular or dependent users (Chester et al, in submission).…”

Exploring causal mechanisms of psychosis risk

“…Premorbid intelligence quotient (IQ) is an estimate of an individual’s level of intelligence before psychosis onset. FEP patients who have greater impairments in premorbid IQ do not display higher genetic risk for psychosis compared to other patients ( Ferraro et al, 2023 ) although those with consistently low IQ have the greatest polygenic liability relative to controls. One possibility is that impaired premorbid IQ serves as a proxy indicator for compromised neurodevelopment ( Koenen et al, 2009 , Pogue-Guile, 1997 ).…”